The susceptibility of the developing nervous system to environmental agents has been a major concern with regard to children's health issues. The formation and interactions between the various cell types in the brain are critically timed events. Such windows of vulnerability is assummed to be a major component in the differential susceptibility of the developing organism to environmental insult. This project examines chemical induced perturbations during development of the nervous system as indicated by various alterations in the morphology and molecular profile in the developing brain and assoicated neurobehavioral outcome in adolescent and aging animals. We have reported that low-level lead exposure during post-natal development alters the normal developmental process of apoptosis and pruning. In examining the long term effect of early developmental lead exposure in the non-human primate, we have demonstrated an association between lead exposure and the increase in amyloid plaque formation in the hippocampus with aging. Additional studies have examined the effects of mercury exposure during development. These studies were based upon reports of altered immune functioning and changes in the brain immune cell, the microglia, in autistic patients. In examining a possible increased vulnerability of the developing brain as a function of an altered immune system, we have conducted an extensive study to replicate and expand previous work suggesting a differential effect of ethyl mercury (administered as thimerosal as a model of childhood vaccination) in the autoimmune prone SJL mice. Using targeted specific behavioral tasks modeling autism such as social behavior in addition to motor performance, immunohistochemistry, unbiased stereology, and target organ chemical analysis for mercury, we did not identify adverse effects of developmental exposure to ethyl mercury or childhood vaccines. Working with the Toxicology Operations Branch, we have establishing a testing protocol to examine the neurodevelopmental toxicities of environmental chemicals that can be employed in an applied manner to evaluate compounds of concern for developmental neurotoxicity. In addition to changes occurring during development, this project will also develop an approach to evaluate latent effects or effects on the aged brain as the result of early developmental exposure to environmental chemicals. For these studies we continue to use a number of methods to examine alterations in the developing nervous system following exposure to environmental agents including immunohistochemistry, molecular techniques to examine mRNA levels, as well as assessment of neurobehavioral functioning.